Total Synthesis of Aminoglycoside Antibiotics, Apramycin and Saccharocin (KA-5685)

Abstract

Abstract Apramycin and saccharocin (KA-5685) have been synthesized from previously synthesized neamine (3). Addition of allylmagnesium chloride to 4-O-[3′,4′-O-cyclohexylidene-2′-deoxy-2′-(tosylamino)-α-d-gluco-hexodialdo-1′,5′-pyranosyl]-5,6-O-cyclohexylidene-1,3-di-N-tosyl-2-deoxystreptamine which was derived from 3 through the 6′-N-oxide, gave 4-O-[3′,4′-O-cyclohexylidene-2′,7′,8′,9′-tetradeoxy-2′-(tosylamino)-l-glycero- and d-glycero-α-d-gluco-non-8′-enopyranosyl]-5,6-O-cyclohexylidene-1,3-di-N-tosyl-2-deoxystreptamines which were in turn converted into 4-O-[(8′S)-7′-N,6′-O-carbonyl-2′,3′,7′-trideoxy-8′-O-methyl-7′-(methylamino)-2′-(tosylamino)-d-glycero-α-d-allo-octodialdo-1′,5′:8′,4′-dipyranos-1′-yl]-5,6-O-cyclohexylidene-1,3-di-N-tosyl-2-deoxystreptamine (25), via azidonitration of 1-N-acetyl-4-O-[3′,6′-di-O-acetyl-4′,8′-anhydro-2′,7′-dideoxy-2′-(tosylamino)-l-glycero-α-d-gluco-oct-7′-enopyranos-1′-yl]-5,6-O-cyclohexylidene-1,3-di-N-tosyl-2-deoxystreptamine and epimerization of the 6′-hydroxyl group. Successive deprotection of 25 afforded aprosamine, from which 1,2′,3,7′-tetrakis(N-benzyloxycarbonyl)aprosamine (28) was prepared, and glycosidation of 28 with 4-azido-2,3,6-tri-O-benzyl-4-deoxy-β-d-glucopyranosyl fluoride or 2,3,4,6-tetra-O-benzyl-β-d-glucopyranosyl fluoride, followed by hydrogenolysis, completed the total synthesis.